MODELISATION ET COMMANDE DE PROCEDES NON LINEAIRES ET HAUTEMENT VARIABLES

MODELING AND CONTROL FOR HIGHLY VARIABLE AND NONLINEAR PROCESSES

Abrégé français

L'invention concerne d'une manière générale des procédés de modélisation et de traitement de non-linéarités en vue de l'application d'une commande automatique à des systèmes présentant une variance interprocessus élevée et des non-linéarités. La variance et les non-linéarités rendent ces systèmes difficiles à commander. En ce qui concerne la variance, on remplace le modèle mathématique du système par un système plus représentatif à partir d'un ensemble de données que l'on peut choisir, ou ne pas choisir, sur la base des caractéristiques du système à l'essai, puis on l'adapte au moyen de techniques d'estimation récursive. Des non-linéarités définies par seuil de réponse et des réponses maximales sont incorporées dans des modèles linéaires associant des entrées cumulées à la réponse. L'invention concerne, dans des modes de réalisation, à titre d'exemple, se rapportant à l'administration automatisée de médicaments, des médicaments de blocage neuromusculaires par le biais de systèmes de commande d'avertissement, de consultation et en boucle fermée.

Abrégé anglais

The present invention relates generally to methods of modeling and handling of nonlinearities for application of automatic control to systems with high inter-process variance and nonlinearities. The variance and nonlinearities make these systems difficult to control. Variance is accounted for by replacing the mathematical model of the system with a more representative system from a dataset that may or may not be chosen based on characteristics of the system under test, and then adapting using recursive estimation techniques. Nonlinearities defined by threshold to response and maximal responses are incorporated into linear models relating accumulated inputs to response. Example implementations in relation to automated drug delivery for neuromuscular blocking drugs through warning, advisory and closed-loop control systems are discussed.

Revendications

31
CLAIM S
What is claimed is:
1. A warning system for indicating when one or more responses of a process
will reach
one or more setpoints, the warning system comprising:
(a) a user interface for receiving process related data including process
characteristics and
inputs administered, and for displaying information including warnings;
(b) a communications interface through which the warning system obtains data
from one
or more sensors;
(c) a model of the process' one or more responses comprising one or more
equations said
equation including a set of one or more parameters, said model translating one
or more
inputs into one or more responses;
(d) a computing mechanism operatively connected to the communications
interface to
receive the sensor data and connected to the user interface to receive input
from the user
and to present data to the user, the computing mechanism configured to use the
model of
the process' one or more responses to estimate current and future responses;
(e) memory operatively connected to the computing mechanism for storing and
retrieving
sensor data and data relevant to the computation, and for storing programs for
operation
by the computing mechanism; and
(f) a modelset comprising one or more models of like processes similar in
mathematical
construct but with one or more differences in the one or more parameters;
where said model begins as an initial model taken from the modelset or is
built as a
mathematical function of one or more models in the modelset, and is adapted by
steps
comprising:
(i) collecting measurement data related to one or more measured responses
(ii) estimating the one or more parameter to adapt the model of the process to
the
collected data; and
(iii) evaluating said model of the process for comparative performance versus
other
process models in the modelset, and replacing the one or more parameters of
the model of
the process with the set of one or more parameter of another similar in
mathematical
construct process model from the modelset.

32
2. The system of claim 1 further comprising a database of characteristic data
related to
the processes whose process response models have been included in the modelset
3. The system of claim 1 where the process represents a patient, and the one
or more
responses includes a physiological response, a concentration of one or more
drugs or an
effect due to one or more drugs.
4. The system of claim 3 further comprising a database of characteristic data
including
demographic data, health and lifestyle related data associated with the
processes whose
process response models have been included in the modelset.
5. The system of claim 2 where the model of the process is evaluated for
comparative
performance with models in the modelset sharing characteristics in common with
the
process as indicated by data in the database of characteristic data.
6. The system of claim 5 where the process represents patients and the model
of the
process is evaluated for comparative performance with models in the modelset
having
similar demographic parameters that comprise at least one of age, sex, weight,
height,
lean body mass, body mass index, race, genetic data and history of smoking.
7. The system of claim 5 where the process represents patients and the model
of the
process is evaluated for comparative performance with models in the modelset
having
similar health characteristics that comprise at least one of heart failure,
lung failure, liver
failure, kidney failure, hypertension and diabetes.
8. The system of claim 7 where the process is evaluated for comparative
performance
with models in the modelset based on degree of disease or disorder
progression.
9. The system of claim 3 where the drug is a neuromuscular blocking agent.
10. An advisory system to advise a user on how much of one or more inputs to
administer
to a process, such that one or more responses of a process will reach one or
more
setpoints, the advisory system comprising:
(a) a user interface for receiving process related data including process
characteristics and
inputs administered, and for displaying information including warnings and
advice;
(b) a communications interface through which the warning system obtains data
from one
or more sensors;

33
(c) a model of the process' one or more responses comprising one or more
equations said
one or more equations including a set of one or more parameters, said model
translating
one or more inputs into one or more responses,
(d) a computing mechanism operatively connected to the communications
interface to
receive the data from the one or more sensors and connected to the user
interface to
receive input from the user and to present data to the user, the computing
mechanism
configured to use the model of the process' one or more responses to estimate
current and
future responses, and to calculate quantities of the one or more inputs to be
administered
to arrive at a future desired response level;
(e) memory operatively connected to the computing mechanism for storing and
retrieving
sensor data and data relevant to the computation, and for storing programs for
operation
by the computing mechanism; and
(f) a modelset comprising one or more models of like processes similar in
mathematical
construct but with one or more differences in the one or more parameters;
where said model begins as an initial model taken from the modelset or is
built as a
mathematical function of one or more of the models in the modelset, and is
adapted by
steps comprising:
(i) collecting measurement data related to the one or more measured responses;
(ii) estimating the one or more coefficients to adapt the model of the process
to the
collected data; and
(iii) evaluating said model of the process for comparative performance versus
other
process models in the modelset, and replacing the one or more parameters of
the model of
the process with the set of one or more parameters of another similar in
mathematical
construct process model from the modelset.
11. The system of claim 10 further comprising a database of characteristic
data related to
the processes whose process response models have been included in the
modelset.
12. The system of claim 10 where the process represents a patient, the one or
more
inputs are drugs, and the one or more responses includes a physiological
response, a
concentration of drug or an effect due to the one or more drugs.

34
13. The system of claim 12 further comprising a database of characteristic
data including
demographic data, health and lifestyle related data associated with the
processes whose
process response models have been included in the modelset.
14. The system of claim 11 where the model of the process is evaluated for
comparative
performance with models in the modelset sharing characteristics in common with
the
process as indicated by data in the database of characteristic data,
15. The system of claim 14 where the process represents patients and the model
of the
process is evaluated for comparative performance with models in the modelset
having
similar demographic parameters that comprise at least one of age, sex, weight,
height,
lean body mass, body mass index, race, genetic data and history of smoking.
16. The system of claim 14 where the process represents patients and the model
of the
process is evaluated for comparative performance with models in the modelset
having
similar health characteristics that comprise at least one of heart failure,
lung failure, liver
failure, kidney failure, hypertension and diabetes.
17. The system of claim 16 where the process is evaluated for comparative
performance
with models in the modelset based on degree of disease or disorder
progression.
18. The system of claim 10 further comprising adaptation of the model through
estimating model parameters by at least one of least squares estimation,
recursive least
squares estimation and recursive least squares estimation with forgetting.
19. The system of claim 18 where the model is adapted according to a recursive
least
square estimation algorithm with forgetting and the parameters for forgetting
are
modified.
20. The system of claim 12 where the drug is a neuromuscular blocking agent.
21. A system for the closed loop administration of one or more inputs to a
process, such
that one or more responses of the process will reach one or more setpoints,
the system
comprising:
(a) a user interface for prompting and receiving data including process
characteristics and
inputs administered to the process;
(b) a communications interface through which the system obtains data from one
or more
sensors;

35
(c) a model of the process' one or more responses comprising one or more
equations said
one or more equations including a set of one or more parameters, said model
translating
one or more inputs into one or more responses;
(d) a computing mechanism operatively connected to the communications
interface to
receive the sensor data and connected to the user interface to receive input
from the user,
the computing mechanism configured to use the model of the process' one or
more
responses to estimate current and future responses, and to calculate
quantities of the one
or more inputs to be administered to arrive at a future desired response
level;
(e) memory operatively connected to the computing mechanism for storing and
retrieving
sensor data and data relevant to the computation, and for storing programs for
operation
by the computing mechanism;
(f) output communication means to one or more drug input means to automate the
one or
more drug inputs; and
(g) a modelset comprising one or more models of like processes similar in
mathematical
construct but with one or more differences in the one or more parameters;
where said model begins as an initial model taken from the modelset or is
built as a
mathematical function of the models in the modelset, and is adapted by steps
comprising:
(i) collecting measurement data related to the one or more measured responses;
(ii) estimating the one or more parameters to adapt the model of the process
to the
collected data; and
(iii) evaluating said model of the process for comparative performance versus
other
process models in the modelset, and replacing the one or more parameters of
the model of
the process with the set of one or more parameters of another similar in
mathematical
construct process model from the modelset.
22. The system of claim 21 further comprising a database of characteristic
data related to
the processes whose process response models have been included in the
modelset.
23. The system of claim 21 where the process represents a patient, the one or
more
inputs is a drug, and the one or more responses includes a physiological
response, a
concentration of drug or an effect due to one or more drugs.

36
24. The system of claim 23 further comprising a database of characteristic
data including
demographic data, health and lifestyle related data associated with the
processes whose
process response models have been included in the modelset.
25. The system of claim 24 where the model of the process is evaluated for
comparative
performance with models in the modelset sharing characteristics in common with
the
process as indicated by data in the database of characteristic data.
26. The system of claim 25 where the process represents patients and the model
of the
process is evaluated for comparative performance with models in the modelset
having
similar demographic parameters that comprise at least one of age, sex, weight,
height,
lean body mass, body mass index, race, genetic data and history of smoking.
27. The system of claim 25 where the process represents patients and the model
of the
process is evaluated for comparative performance with models in the modelset
having
similar health characteristics that comprise at least one of heart failure,
lung failure, liver
failure, kidney failure, hypertension and diabetes.
28. The system of claim 27 where the process is evaluated for comparative
performance
with models in the modelset based on degree of disease or disorder
progression.
29. The system of claim 21 further comprising adaptation, of the model through
estimating model parameters by at least one of least squares estimation,
recursive least
squares estimation and recursive least squares estimation with forgetting.
30. The system of claim 29 where the model is adapted according to a recursive
least
square estimation algorithm with forgetting and the parameters for forgetting
are
modified.
31. The system of claim 23 where the drug is a neuromuscular blocking agent.

Description

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PCT/CA2007/001605
604-732-16 17 February 2009 17-02-2009
i
AAOD"t3 AND QONTltOL FOR H[GBLY VARIABLB AND NONIIIfSAR
PROCBS4B3
CROSS-REEBRBTiCB 7ti RiLATBD APPI.ICATIONS
S[ge01] The pres t apgiiaa6oo chiaos prloffity fitorn t)nioed SMUS Pmvn=a PBUM
spoiCetion No. Saeks! No.: 60J82S,903, filed Sopmembar 16. 2006.. aad frac
United
stma PnNbiona 1xbm aPPbafian Na 60B25.9oA. filed Sapmmber 16. 200b. aad
puesned ea FCT applicavona P(R'ICA200riA01605 and PPC.'PlCA2008JOD1606.
t0 BACKGROUND
(OM Many poodew hm nWmearities suAlos e:imsme ruiatiw baamaa baLOhes
(or otm or aqmdmm or aubjecta or aoarwiee). nd tbis malaes tlm aumansrio ctf
tbeae
paoca~es wy ditPicak. In bio2ogEcal s7sftfn& 9al"nb}aa (bmmen. aam-hmYUOn
SIZU1104
tiout ar otbar) vaoK}aa is lerge. Pammeess deecibdng spoase to inpan
(eleatr+mil.
13 sDanicd or otbwwiae) vaty $:eWy wrimia the sause apeaiea, rvith vaiadm of
as maoh
as 90196 being camnma
[ooac3) 'fie otmM aewrigtsoo, wMk :ipp]icabte wmy proeoas ccmtrot sysmo
diepdayiog nubmw bftvias mod vadstiam wffi dr4eloped thrwgb woalc dono in
enDUpaated dtng deHvrxy in geaeml aad wooareod delivexy of aewomuQSVltr
blocldng
20 0040) dmp in epe.csoc. 1bus, the sxamp7ea -d inoany,ttWm ptr,peled svM
eo~oeevm on suummood drng dclivery. IU folloarlag discwaia pmvideo aPneral
' d i of cxttaia aapects of the backgrmmd and whik ineoncWvie does not panvide
speeific Eactuat rcpsscnmdons.
(gW47 Antamated diog delivery (or a-g admWiawmon nadar eompaw gmaLnoe os
23 ccntroi) e- improve dtug thttapy by allowing ft Anore cflkimt end smoot6er
delivay.
Avtommmed dea$ drHvery may reduce dtng wRg% o8e eFfeds md ooam; paanit beatth
c~e staPf ta wmk mae affiewntly; aud allow ft udo we of diap that are diffmtt
to
ado>biaw tn+uaD9. )erd'iag to betta eare for ttia pati". Computer oa troried
mftiais~iaa of bosul . blood preswne amdicaSom neoromuewtar blocking (NMB)
30 agem and atber draga bas beea at6empted ptaviaauly with 1iodted tpooees.
Applicman
of conVww oo 401 to NMB druga is aric6 field, aad a sabja.t that is both firam
weh
nonimeariiiea in napomee and with gtse nw- and bm-pmtlem vedabiBty. Cumpuoer
iqbE6IDED 3$8ET
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2
txsRro) of ittlS dtags wiA be ftcusaed betc to ilkuoinate Hte difficaltiisa in
COWORtt$
tbece nosliosar and vaianoe-Ptom sYamema.
[OOOS7 N11B dtugs pnoduoe paralysis to prevetst motiot4 peatnit teaeheal
Webaum
and allaw atxtss to deep struchues wAh wnallrr incisions As NMB dmgs ltave
tngh
5dxrapecdo indices in hospital setting% they am often used in eacess of
atiniaml
efFzctive nsqnirmtents. A strnLegy for administtati0n is to provide an
overdose to
PmdwB pualyna. nwmw ibr ntuning muscle fimctioa and, am it remtn9, ovadnae
again [1].'ilw laW dose delivais rapid onset of paralysis. qtpckes surgical
coadftm
and avoida titratiats to a precise anoatRetio arqoint and regubdion onee there
[2].
IO [n0967 The ptactioa of ser{tJ bo{us adn"sttatirnt of NMR drugs laads to
iastaaoos of
undar- and owerdosing. Overdosing is itnpottant at the end of the csse when
the p~t
should be extibated aad awakaned, but caw+ot be due to the presence of too
zrnrch NMS
drttg Overdosing ar.ates dalays wfiile the 1VM$ dtog aroszs out and dae ta
itnptoper
mnommcww mooitoaing, tesults in a cat many pa<iefõs beiny exttitiatedl
prematureiy.
15 Incideisce of post-opesntive tesiduai ctumdzedon (PORC) ia between five and
10% of
Pancras fos itadmedate.acting campoutuis, such as roouivnium (Eritcsoon [3]).
and
'betwxn sboeea and 42% of pstiaits will have To4 aosastuemente of less then
0.7 to 0.9
(Mm'Pl+y [4)). whict can Icad to impaired hypoxic verKils2oty mspmse and other
complications. TU uKerdosing suategy is aiso. a soatca of inaenvenieace #wuld
20 caunplica8ona arise and the su+gied conditioes chaw, which is not wworamon.
JUter
patalysis and tnchseian have tnkm plaoe, examinatiwi of the patietu msy reveat
a
tomplitatiau mb as txtamiw invaaira caocintmw, wbieh may seguite diffatsnt
staff,
eqnipnieet and procedures. t9tanges ia staf~ equipttsem and procednvea will
iead to
caaceDotioa of the scheduled pcvicedtro, and the enaAhesiologiat aad atorWing
musea
25 will have to wait untii the NMB wem off enoagh to allow revetsaL
[AW/] As anotlw example, in Haeritoon rod iasertKm for ttsehagiog the opfine,
tlhe
surgeon assesses whether or not the tuck have irVmpd nerves by the abiiity of
the
patiwt to respond physicatiy. Testing can be perfmmed only after the rehao of
mnecle
fmoction. Automatie control oould keep tho yaticnt ]eas paralyzed uotil a teat
is requind..
30 reduce drug adntiaistration oo aDow futxDm to mtum, aod tUea ce.paratyne
fer
continued worlt with less waidmg tirne by the surgical staPf.
A14mID$1) 9ASET
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3
[M] It is jw4m to evc3d an8erdoaeg dosing the eara at it ¾aon be a soaroc of
Wfta.,op=Wive adMae aventa. Palimta wilh ineffective Ieveis of NMB wlli oottgh
amd
buck On ihe veeblaoor, pow"bly rteuhmg in eadinsion of inoe+nal aagaee. asd
aill move,
posmbiy resuldag io injury fraan a16er means. As well. mesciec witl be tighDet
and will
ieaist mrgjcal interveal6offi malang the eurpoas' job maaa d'dfic%ft
jD009] The probfems associated aifb serial bodns Aosing aw iaacadfiod due to
the
M+ent paacdoe in m=imriag oF MAB batag deficiam. 1n an ideal smwK tbe pstimt
vrauld be maaitorod continuously tlrosgbout the proeadura so that the
Aneadogalogiel
ued medieal adsff wou6d be eu staatty awaro of tlw ata0e of the paema mnsde
faac4an
aod waWd be able to pavide Wpmpdm anmmb of MNB dntSa to amiuUda tbe Dvdaat
at an ideal level of muack fanctim dKoushout ft pmceduro. Howeres. oantinuous
HI-B monkeiog by fhe anooheddog}st ia la6or inoeodv+s for aamoaue vvbo - for
ttie
bmamed of tbe patient'i health - typAeally oamot devote themenlvss anlely to
00 NMT
acnsw. 13i9 is ane rea om wby obJeetive noonimiug is nat done eontamously. but
1s insrsad eitbw only at ioey points in the case wcb es exmbatiao, or not at
all. Computet
aontrol of NMB caaild nadaee antsMc"ogW moai0oiciqg af muscle ceapotue, tedaee
60as of [avasibd6ty at pocedune's end due to over=ps<alyat% and give =W1,
6ne control of musrJa tone. Repoesentsdve control eflkm inelade baeg-baog [5],
ptvQotfiaual Integtai Dedvative (gID) contaol [6]. PIDfSrnith Ps+odieme [7]
and fnzzy
logic e0mo1 [91. 3ame of Ou cenhoilas derdaped kape aot boaa eteble or robust
onongh to 6amda ft iotea- ana fnttr-pationt vadab114y peaant,
[0Y1A] Ot>m cont<o0cra have achieved eear eaaetm levr.ls of bloclmde in
relaSively
caatioRad axpaimewsl eatdags, but am assocued with sfgoiYxant canaEnints tb.t
tima
ft have impeded thoir atlity In rontina olinieal pn>de. Far azample. mort
iovotve dio
use of siipe trvitob aflmulaBon to maasuco vesponm (ST or T196). fe addkbn to
the
often crosidemblc associsbed Qetup tmr, &e use of eiuge twitch sftulat~a
MMM&Ms
a dable cnn0;o1 {9] aad T1% baeolme etabEasaaa re9uines up to 20 miaotee
6etwaxp
io&ction and NMB drag aftinisttation I107. unneceseaaly pxpodag pattt~lc oo
the
asts of an uuprooected aicwey mod croeting tmaeaeptable opamft toom time
delays.
Rudiermaaa, ft typiat conoiollx setpodot is Ti* = 10% (.e.. 90% siagZa twitch
auppnoaiao) IB. 10. 11.12] wbicb tapaeseats a potendaffy nonqvversIble statc.
A140mBD 9888T
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4
[00111 Adaptivee coadul smy belp accommodate ft patkat vaaeacx: An adaptivc
coeavIIa usually oomWicea a fucod-strneMe cvnarolkr witb adjuslable paraoxtas
and
a merhawem fni sutomaBaatly adjusting those paiametera. Adaptive ooutrbl's
mots
bzgio in the 1950a with die davelapmem of the wtopft for liig6-perfommloe
airolefc
5[13]. Siaoe t~an tlm has bsen much 16eetical develo-ment anA applioetioa An
in-depdh n;view of this 5etd appeais In [131. An ezamplo of an odqdve cwauol
oxhaique 16ai hes been aeod not juet in chanical basoh proceBaes but in
clinicsl
applicatioa as well is (leaeralized Pcodictive Condrol 114, M. a gead8)-
pnupoae
adopdve ooafrol method. 7hia axdwd was used 'm tAo opareiing room in oontm] of
NMB as dearn'bed in [161= .
-PAT@rf DQCtJIVETTS
[69111 See US pataat noa_ 2690178. 4080966. 4280494, 4291705 4370983, 4392649,
4533346. 4741732, 5256156, 5335164, 5404456, 5520637. 5713856. 5822715.
5957860. 6042579, 6166977, 6328708, 6379301, 6389312, 6511453, 6599281,
6605072, 6725086. 6796956, 6807965, 6830047 and 7220240: WIPO 93114807 and
0i1/67820 ; ad US applicativns 200E10217628,100310136143 and 2007=55135.
HRIBP SUMMARY
[00131 Prescntcd bae aie mahods, ayesema, etc. for roducing varisaon and ft
effect of
noalineatiaes to facr'lCtete appticesion of adaptfve control m pnaoessw with
nanliaaarJaes
aadlar vaelgdon.
[OOf4] ltlonliiieatities can be accounted for by caeatiog i non-dalayable. aau-
satidatabTe
response oI I dset folly repnesms the nan-1iuer model diraugh its range of
linear
eeaponse and t6eu adds compolown iato da nwnges ia which Hte saarlieem' model
connot pmdaoa xesponse a in whi,ch tFw nonfioear model produces soturamod
iosponee,
and in this way all inputa can be mepped to an outptit. To aeaee these
tnodels, cespnasea
to s9azderd impulses we r.cotded ft ono or moue procusea SaMarted mid
unntl=ecxed
(zaio or 6aseline measwem=) respom;e measu-nents ate disearded. 1be rz. ng
poiots aae sdjusssd by aesliag them to be a pmopaCtlon of che rmge of efFeee,
and thee
add=mg to 8mm an offset to acc.oant for dx tresWd mas neede to be achieved
beto~e
efioar is sean_ Lfsintsnupted curvu dasca'bing these responses can be arrived
at dvonA
AbdINIDSD SH.EBT
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aaived at tiuough a curve 6lting esumatien (eitlw Hnar or uoo4jaw depending
upon
the liaearity of ehe undedymg eqnationa driviag the p~v~es) of the noo-samuoea
wspoose pcists cmidatod to the tim s3nce tlr, botas doss was adminifts+ed The
uniutenopsed catves are linear modeb of ft pcocets impolse msponses sad cm be
used
5 as flaiBe impulse Fecponses or ooa-oroed to t:mefar Po30tlon ar stase spaee
amodels or
oebeewisc:emadeled as desi~Ed.
[OolSj Intsr-procross vasiatiaa can be accoanted fer by antssdtu" for the
model m two
ways. 9'he Stst way can be a Oas edaPsl{oo ia whioh tLe ooefflci00 moftnag tbe
paasmeoeis dcfming Ihe ongiod snodel an isplaoed w+uh eoofficlemb of aaodxr
model
found ft be morr repeseaotive of ebe proceas beiog modedod, aocering to ooe or
mone
measmed mpossos ,jodgod againat tlse iaput or mpuer Siven oo tlw pwaL The
subauaaoe model ooeffldenta cao be nloeri Som a mait:tude of aets of model
eudfidmb
(haeia safared to as tbe "modelset'') tbst caa be pse.eompoled fcom prsvioaa
exper-eKas, paaan cesea ar otlm moasmmem or etber iofamudion or oalcvhtions as
deaicod. TU aecoed waq of accoundng for vadadoa ean be a fine adapletiom where
linear teotmiquos soch as mcmaive Iease sqames ardm2hon (RiSE) are applied ta
fo8w aaee the coefficients describiqg the pmms towmd tbea usa values.
[0016] Ie aac embndiment ft metlsods, eic., discosted beasia en incoipoiated
imo
control of a ptoeess having high vadabality aod noelaw sCtioa. Tbe ptocesa run
is
suaed wilb t6c computa or o6arwise belkviag the psooesa to be an aveage
prooess.
aad inputs m+e givea to ft process based on dw iufbenatim to try to move the
syekau
sate tu a staLe sucb tLat the desiied eatpun ace 4ad. I-lEei 9=0 inpUN are
givaa the
imtiel dalay to action is paseod aad a:spoose is aan BvanuWly eaough
auas<ue2erlft
am oleaiaed fhat te taleoIadon method fbr dctecmmiag a suiuble model can ba
madc
and ft set oi'aocticicote deeraat ng tbe model ue nplaoed wits a mcae
appnViate sei
With every aaw omesoep. ipR. ootput and syetem sESta data atz geoaased aod
RLSS ia
applied to ume t~e model cloaer to ft teue model as a fom oE cOntinum's
imPovemeat.
Wrth thie condnuoos impmv eat tte inpjts givoa beoomo mme appeWriate, ft
omputs boewoe claser to aAat is deshed aud ovaall pertoanaoee ia impeaved.
[OO17} fa saethw embodiment the metboft etc., discussed Fseaeia aro
incocporMed ino
an advisoey systern in wbich the ispat is nOt givan directly by ft omputer,
but is
inslead gi.rc.a by the ase[. As in ft previooa wnbodbuM the napoese I. sansed,
the
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of giving the mpatar the aaloutation remhs can be pmsented to the uaa as
a&rioe md the
user can decide vubeiher or not to giwc the inQut. For a dmg advisory system.
advice can
be provided on how mucb dmg to give and wbeo w give it The usa is geeardly a
health pmdlcssi~. ench as an anesthelist in an operating sooan, but can also
be the
palierjt if the diag and advisoiy sysoaa ats nsod in an ambulatory sdang.
[oo1g) In another embod'imant, the accoumtng for eoelinewities is usod as a
metlw of
deoaasinmg drug concxotcao.oas wi8cout use of blood sampling.
[0019j Ea anot5er embodlmeat, tbe rnetbodk e,to.. Pzedict ldoefihoad of
tmoblema in fbe
piooeas based upon tbo reapoase sneasoied. For example. based upoa a slow
iespoauc
re]ativc to averW psoxsses, rncwenmdatiams mighc be made to invessigaft the
cause
aud/or grovide pnveatsave mairftnanoe. As anoNer exampie. a dicease state such
as
livv os mnal function c6raknbhmerrt may be pzedieoed in a petieot based upon
an
aboamaIIy laaig drog essideocc tinx. Recovnnandetooe can theo be made 1br tlie
patimt to uougo cGsting=
BitEFDSSQtIPTION OF THE DBAWINGS
[60211I FICI. 1 411uaualos a dieeaete dm liaear I.aguane aadal (modiCud ima
1191).
whe[a N is dm number of fddecs, a is @ie Laguern polc, z is the discrete tinre
Earward
operatar. ls ia the I.agverre vectaar ooeffciems ead q Rpsescats t1x l.agueare
8aine =
[OQ2l) FIC}. 2 iUusmam a relationship betwean blood coneanumaa of a drug and
eeapamse over time. Graphs ane oreriappod to show dmt response Is not
obmervable onu7
a acruin tlizaahold !ms beae reacbed.
[Mtj M. 3 iIIusLales the modeGpg process wAere respaeae dala is ooaveated into
psevdo-oca;=cy data, modeled as an impalse sewmm asad then rnodeled as a etale
spaoo aiodel.
[00231 FIG. 4 illastama a block diagram of an advisory sysoao.
[00241 FIG. 5Wasumn a sample depiction of the NMSAS display.
[00E5) F7C3. 6 i2lastrates a ncodelmg psocedure of model replaoenKat and
adepadon.
[U026) PIG. 7 iAueaates a mndelhn proeednre of model replacement and
adaptatian
with sabgtoupa.
[0021) M. 8Moati=ates a mndeling prncedme viewed scheaoat4cally.
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7
DETAnBD DFSCRIPTION
[0lgBJ '[1te followipg dmCOgaioa begins vvith adscuss~e of aqaflnearbes aed
how titap
ets >smqpd and inoatpmated 'tntoaa exemplffiy saitable model. A dwelopaneot of
the
S modalsaa ned for gtoss adqXab0o is disaanad, aad thea, a protxss of taodd
adaptmdoa. F'inally. eeslaia em6odnmem will be disa+ssed.
I9w Fmoeas Mosntasing
[nCiO) whea coomnofHnB of a Pmesa it in bmefsciat to know how tbat proxss is
tescGng to iaprt in aIn to cmmcdy adjast ft iapat, or inputs, to produce the
drsited
outpot. To kaie bow ft psooess is teaft& seesaas we used. Pot autotaased drug
at)mmdstwtioa, thenc ana a gncat many scnsata to tneawze reWotn to dugs.
lieact
fmxdoa is asseaaed by eleet:ocatdiogram (ECt3); b,tood par,swn fs detealmood
with
pmessate omadtuoen; aad oxygea sdotatioo is deoeradnd tbroagli ase af putsa
oxymetty, to t>ame afevv. For tneseatemmt of zzurommatlar teWome, the aeasor
stoma]aLa+ a nr.rre to evoka eonetictiem of the rnncle iamcva0ed by " nwve amd
ft
oeatcedien can ffiea be measomd. Odur semsoss can be used for aon-aurgiQel sad
non-
meditxl sibmuoas, soolt as optiCal aeasat% d,igiMl satsais saeh as C(Ds,
t3ldfSs. Cms.
ete., as wall as specoogtapiuc. nasgtactic6 pmeasuae. Geavetaune aad ot3rer
ssneots.
For nemomuscnlar response mwaceanmt, ft moet commonly used ooozomsnacnln
emazog ntodatit)r is the ttam-of-fonr measm+ement {TOF) by elecuosdrmhdoa. 1be
7W nses foaa bnef (betaeca 100 and 900yts) c0atat polses (aa&4trmm of 70bnA)
at
2Ht. iopoatod Cvety 10 to 20s as eleateodOmNation.'1Le tma;ulting taiteIes ate
mamned
aod qmaoti6ed foc eleaaoaryogaphic rosponae, fo,roe, aecelaation. deAaetiaa
oranatber
means.ltts fitat and laat puLes paoduoed m+e comyued and the ratio of the two
gives em
estimsoe of the level oP nenrrnnascular bloalcade. Other oomnon stiuadstioa
tc~ques
inoLade the ainglo twitch (ST) and pest-tetenic ~(PTC). The ST measuremestt is
a
amgle electricat pulsa of buwesu 100 and 300Ns. tepeaeed at uNetvals reater
thaa or
eqoai to otte eecoad. Al teast ioor seoeeds is desited betvraaa stitaaii so
pnermt
ulaeQulation aa8 aloera4om of the una mmscle sespoose. An ST tnessatement
taireat when
the atitmdatlou asgime is firK statled is iecaded as ft onutrol. labeled TO.
The ST
measuszabem is a tstio of the ]atcat neawted musele twiteh eompand to tha TO
vahu.
PTC gtimalatioo is used in deep htodude n a ttrotms of evokiAg a IaMge
orntoodtnuiaCos
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8
tempormily the MMB. It coosists of a smanus at 30Hz for five aeoonds followmd
by a
tbaee seoood testing period and ihGn a chain of up thirty ST impulses. Tke
nomber of
impulaoa that ean be measored itidicates ft degrae of blooicade.
[60321 Model+ng
[090Ct1 In order to estimete levels of &ng in the patieat and corTesponding
iespoRse,
both at the ptrsent and in ft futane, eha eonuoller needs a tttalbmtatical
datcrip aoe of
t3w psoosas and how the pmcess reads to iopats. This description is ft pexesa
mode7.
[OM1 Proeesm can oflau ba descdbed arM dttferontial equatiaaa. T1am aquationa
caa
then bt forneed itrou state apace modele for vvhiab a large body of literatum
has beea
dea%Iopod for solving aad ditedalg tvwatds eonorot applicat6ons. known to
those aware
of the act. In bticf. a Benwal famat of a atate space taodel is:
r4t } 17 ~ .a rf+.j } ~ a~t~
a(ti c f'a'i!1tPaift rl~l
where a is " inpat, y is tbe ootp<tt, t is ft timesttp attd x is the state
vecw, and A. B,
C aod D are tlYe ataee. iopot, output snd inp~rt-outpnt dine¾t coupling
metrices.
[90061 An advardaawns form of model fas administration of drugs and one
sipular to
tho state space model is tho laguate model. A I.agueee model is an omthanormal
acries
repaeaat,mtion of a pleaiCs dynamics. consiatiaY of a saies of ftlte:s, tbe
ftst being a
low-paaa Ater aad snbeeqaect filtas beieg all-pess fiitam talung as uqxa the
inpat to
ft syerea, and producing an eatimate of the output. lbis ie displayed in
iignne t. Ia the
figura. u is the iopar to tbe ayawo, y[s ft outptn, N is the number of filtem
a tbe
i.agoeae pole, z the dis- ete tiaoe forward operator. l, ft Lagaea+e veetnr
coefficienta
which malce up the x atate vector of Equation I and ci tlie I.egwt+e pins
which make up
tlee C output matrix of F.quation 1. Tbe mabi.ces A and H ate dmaisiomed by
the
twmber of fllters and defmod by the tngaeria Fittar pobe a. Tha Laguase filter
poae is
optimized for each patient model by a]imear aea>ch algorithm to pmvido a best
fit of the
impulao response data. The C vector peuaawoers are also iadividua] to eaoh
patient
l.agtterne modela ffie nsed fat 8adr convardnnt network realisatioi% transient
sigioal
simila:ity (impmtant !or mpoma9ve p>oeess cnaol). aed similarity to Pade
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9
siaoilnity fmporttant foir respandve ptooeas coouol), and eimihriry to Pade
apttoaiaatioa nacfal for idearifying time dehya. Iagoaae arodels have a eimple
cepseaentation and tkjdbte sttoamm. allow-ag for easy adaptatioa [17].
(60357 Modds of respoak to phnmaaoacicals cm be aasoposed of two parts. T1W
fiat
pW is a dmdpkm of the Erug flow ftmoO tAe sabject and ia VmMally a IinM
oSdFaeaaal epeon (an8 t6eseby easilyr ecoretted io4o 8qnatiom 1) of the fwm:
x
e(t) z 'Ea6a''' (2)
whae c(t) ia the wncembign of the deag, a- is a gpin and 7y is the dispoeition
ooas~nt
for tsse i eomparunent, end N is de orft of the carpeanueal modd used to
modal
ft drug. For oxample, t6. NMB rocmoim is commonly modded by a Il1aA ader
ooaMenW enodel. The secamd part inooipocatns the eonlineaitieo arkh an
equation
to eonvaR t>be conuenaaoa of dtos pee:eoe to an effeot :elated to the direB
Pmm=L
Nonlineui0cs aa inaoducod tffiongh mich tbiags as delay to activkyr amd
setio~t[on of
tlie renaw aodlor ompat Lm tlw psncxsa iopat aematax; an ezamp]e of &s faQmer
is a
wa0er tap being oponed only after a oeat,ia nnoamt of Eoma is applied t.o it;
asd :m
exunp6e of the latter is tbc inabft to 9ecieare ft flow ostoe the tap bas beea
fuRy
opened-
[0006] la eome mobodimcads, nodhncuum ne aceuvatad for aad the' ewntio s
repseaonft the system asa liuearized to allow tor appheoau of Iloear adaptadoo
a]ganthroa. Linear ecpetim 1ffive tfia benefits of easy compnbrtion, direct
aolvabft
and guaianteed solatim We4-eablislsed teobmiques for canaot aod adepmsion of
linear
modals eriet and am proven.
[M'/l Simflar to tlte water tap e:ampte, when dap ane admbduene, meaanremems
cem axptciwce nonliaemi6es in ft fotm of dday to aotion and eaauatiOn of
iesponse.
'17tese accUmearities are mLod to die phanmacologioal terms of poraiey end
affiwcy.
Delay can cxiet beCause it may be aeeenay to agurdze (antagonize for blocking
dmgs)
apropmHom of iecxpton befwe napanse is seen. Mu appatently non-opaadonal
pc+opontion ia saQntdmes Imown as ft 'nccpwr teaave" or "satety faet+e.
Samration
wn occur becauae the maximum tespwnre has beeu met by agonizing aII the
rooeptma or
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MatitenudicSUp. tbese nontmearities cen be seen at low aad high wben
effbct as a funttion of drug concentrafioa is defined by the sigmoidsll *wged
fTiU
equation:
f1
E( ) = E.u'cR +~G (3~
5 zD
vvLGVe Eis effcct. B max is the amxianan effect possibla, c is ft coacmtratioa
of thc
agent at the e#fect site. Y is tfie Hil1 euefticiast convaporAing to the slope
of the eurve.
and b'Cso fs ft efketivoe cmconvadop paadaciAg a aesponse509b of the ratimtms.
10 [UXPM 7'6ese nonlinearitiss can be aeen in Figttar 2. As drug is:dded to
the patisat, ft
drug is di9ttibuoed thtoaghoot tie petiaat and the couaateatiatt at the ragion
af intiaest
begias to rise At first dfea is aaa 1]tea after ft drug baa evjeined enaugb
rocepeors,
a thtesdold is reacbed and effa:t atatts to he saen. Effect incanases with
ooacoutrsimn oD
the point of sattuetlon of tbe respanse (andtar seosW after avbicb ft
aaeaaarable effect
plateans. Cancetamtion can eosdnuc to rise but theoe is no iacneaee in etfed.
Con duiag only the prrnmary aexioo of ihe dmg and neglectioy ride effects.
conoentratians above tlue {evet pradax no greater etTect but antead just
aztend the
aawaet of teuec in sawuatioas Meawaable fimctioa rohutm with elirnimtioa of
16o eaoees
dtng. ?.ean tlfeet is aoan agein once enaugb dmg has been dinrinatod tltat
tlaz dwct-o1d
lcwd of drug teceptors beaoate fxe. In the cau of N1V)B d,ugs, tlx teepmeee
aftsised is
cOOuadioo wh[ch will have a xeto etfect level of 100% strength. As the d<ng is
an
antagoaist, die raapouso cm be thongbt of fn opposite tenns. As drug is added.
tetaxatios (the opposite of cormaction) inetmses.
[000] Tbe oeornmuseuier junction (1OI]) is aa exmaple of a syaa4n with
rooepoor
resetve. 'Ihe N1vII. where NM drugs ed, Daa reseeve secepoors to irxerm
ptobsbitity
d eenesotioa on stimdation md decmaso likelilwod of bloclme. It slao baa a
saduarioe levcl in t}mi an iofinite ataoant of force camwt be gewrsfod, and
with mprds
to administ<ation of Tiir18 dn-ga, afta a cettain pereeatage of tlte tecepmes
are blocked
no centreetioa caa be dad. In [18j. isolated cat antnior tibialis and
aattoriaa muscles
wae dimulated in the pnGaenoe of tolae-uarioa and ottur AIIMB tlrngs at Irnowa
eoncmtrealomt. It was eedmalod t'hat 76 f596 of ft receptaas had to be blocked
by the
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l1
conxdom. It was catim.oed t6ac 76 t596 of do ceepom lai4 oa be blacked by tbe
euagoaut befoa+e blocit was aadoeoW and 92 f169b of the reoep0ois hed to be
blodced
tbr aeer coaepleoe blockade. [004i] ia sida4ase io weieh a compauer or otlw
1~'kn cdmdation devioe is mod to aid in
S caladaciNg atd edndnistarieg the deag a at>w inpats. tbe epecatlc delsi3e of
tioe
models, meL aa tine emct values of do paramdms and eoofficiam ia ond in
Eqoatiaau 1,
2 e d 3, vri11 most tiioeiy be ualmaae vbm the pooedae is fint s~n oed.
Ias6ead a boet
gness at wlasc the valnea am ia uced. lbis aaeas ia moaIIy the yaramelees
leaened fmm
prior testing, and can be a popuWm avrraga ShooW the best Snese differ emmqh
fiam
do values of ehe true patamatas, tluee aviII be di>fkxft in coenniTmg tho
panoeee with
ecm aad/ar iaatabTrty as a reeult
I9oti) >tafcmmces.
[0042] [1] D.A. liAJ. Aabvzy. S.J. Rimmer, aod M. blemd. ]daadfiCetian amd
ccna+ol adMuaMe-tda:antaaaeodlesia iBEPtooeedin~D, 129(4)-136-147. 1982.
[DM [21 R. M-[ta. "PbwmwoUoetict of Iviuscle Aelaxanu md tbeir Antagooisa .
chopmr 11 of PlucmaccUmetita of Aaacadmia. BLckwtJl Scimtid'ee Pubficedoo.
198t.
[OOM [3] Ll. Erilrsaon. ReadOSl oeu+nmmcntar biackade: facidwce a d :elerauCe.
Aoa=Oesist. 49(Snppl7 ):S18-19, 200Q.
[0046] [4] G.S. Murphy, J.W. Smlml. J.H. Matymoa4 M. PraokGe, UJ. Ava=n, and
1.3. Yeader. Readad Patatp4ft at We 74ma al 1hecbal F=xwbefiaa. Aeeaalroos and
Aoalgesia, 100:1840-5, 2005.
[0N6] [S] C.M. wait, V.A. (3ost, and C.E. Blogg. Beedbwfc conool of
oQaroasoscoter
bsockede: A simple t7a~an for mfaaien of atracnriam. AmesUmmia, 42:1212 1217,
1987.
[A@t1] [6] H.Ii. Browo. J. As6ary. D.A. Linhass, R Pedc, aaA bl. Anftoy.
G7osed-
lnop coatnnl of muscle relaratioa durinS aurguy. Cljydcal P6ysics aad
Plrymotogical
hinwavnwo,1:zaa-210.210.19ao.
[0049] [y1 D.A. tiutem. M. Menad, and A J. Asbury. Smith pvedctor ffid se]f-
tuaing
coMml of maaolardaxsat dmg admin[wraoioo. IE8 p:ooeedingd.D. 132(3):212-218,
1985.
[0049] [8] D.Q JKaooa, JJ. Boas, N.D. Bdwsrde. DA Liatenss, and C.S.1teiDy.
Self-
Learniag Pnuy Contitol witb Temparal Kaowledge for Attrcatium-Leduoed
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12
Nieucomusonter Block during Surgery. Comprtets aad Bmnnodicai Reeeatch, 32:187-
197,1999.
[0051] [9] 4i.li. Ali. J.E. Utting, and T.C. Gtay. Quantitative assessmeat of
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arnidepolmiring block (patt 1). British Jounrel of Aaaeadmia, 43:473-477,
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3[0062] [10] P.M. Schunaabcr. K. S. Stadler. B. Witz, D. Leibund8ttt, C.A.
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A.M. Zbandea. Model-based comol of neuronnnscalar block using mivaeutluae
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nOtacminm.
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of
aaaomasettlar bloclade. Control Fitglwaiag Aactioo, 6:1225-1231, 1998.
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(OOd9) [18j W.D.M Pamn and D.R. Waud. T6a margin of safety of nearomusa,le
taommisdon. Jomael of Physiologlr, 191:99-90.1967.
MM] 119J O.A. Dnmont. Y. Rt, end G. Lu. "Nooliaesr AdapBve Getetaiiaed.
Pmdietive Coiuml tmd AppliCetion6", finm Advanoea in Model-Based Peedielive
Conorol. Oxford Unnasiry Pms. Oxfotd, UfC, 1994.
[0061] [2()) D.M.J. Qatsod end P. PemuPaha. RoCeQtw Blocimde satl Synaphc
famctioa. Journal of Neoral7YSnamissioa, Suppletnente! 18:61-81.1983.
[0062] t211 P. Pannefat6er aod D.M.G. QaaslaL Relation bdwxn synepic recaptor
3a blockade mid nsponae to quanfal uansaiitter at We mouse neoromuacalar
juDctioo.
Jouroal of CGataaal Physiology, 78:314-344,1991.
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13
[00621 [22] M.E. 5elgada, G.C. [ioodwm, and R.B. bGddlebon. Bxponeatial
Po[gftg
amd Rexuing. Lftmoood )oacnal of Coucol, 47(2)0471-4gS, 1988
[OBf31 Bemoary Handliag Responae of Noalimmi4es
5[6064] As sWed. nonlinesritics ariae thrangb wc6 thir4gs as ddsy to actlviry
and
saatcuion of the sansor andiorowput fivo ft prooesa Input actuam. To
iacorpoole ft
ooaJineatitics into a Iinesr model so @md limar adap0.ve modeGng feehuiquea
can be
appliod, a tinear iaLaaos6ip of reapomse md uecaptas oodtpansy aas dcralopod,
calkd
"pseudp-oocnpeney". Paevdo-oecopency as appfied to aam-deog telated syswms
typdcally doea oot erJa6e to tLe oocapaney of tieoeptis aiacie meup sysGms do
not trave
-receptats" bm doea apply to a fumdameo<st aspeet(s) of ffia pmaexs mlafiog
autput to
iaput and will lypiaily be mffetent in aanme but not in concept.
[U966) Pamdooocupaney is a fineae9ied veraion of tsue receptor accupency and
is
analogm to ft deog cancenuafion at tha etYecmr siw e.g. the NNdJ in easa of
P1M8
dengs_ This )3aadad mOdel of oceapaeey imdndes bvels g~eata thm 100% (with a
raq e of a to infioity) allowing tbr exoeseive doses larger then what is
aecessa:y to bind
atl of tlce receptors, and accoundvg for 16a exee.ea drng and how it ia
matabolized.
Psendo-accepancy c+m be eonsidered a oDW of hea maay maltiples of the amoLmt
of
dmg to bind to all of the reeepton is greaant at she elTecoor sia. Rsspomse
dota are
convaoed to pseudo-occupancy as
paeudoUoeapnaev _ "eayoaae x ~ f~ Ta~ + {I~rra/wtd
1- fArdhold
~ nespoAae x , + tl4realroid (4)
wfiare mm mapanse is !he maxima) nipem mcaawble by do eeaem being wed (cc a
w mmimom fortAe sema+or, which cau be leas gsn 1ha sensors aNimaa seasitieity)
and
tLreelsold is tltie pseudo-occupancy leve! at whiah t1+e etrect prodaced by
eho iapm cm
fitet be seea.
[06661 Pw adamusEntian of 1VMID deags. tha awaaoa] effect oowts vehen eiffia
tireae
ane no omne frec receptms or wLeo the s=saw is AUased aed no hmgw reg'+suus
iaponse. A suiteble value far tha tb¾esLold wae foood through a aoal9eeer anve
[iping
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14
of dam frm 120. 21) to the Ecgmdoo 3 fas xeqwosc to ST ctimulatioa at tbe NAYD
a6cealiog to the propoition of i+eoeptois fne of dmg, mnlting in;
rc x FR a FR17
FRa,r +O
where FR is ft ptopottioo of ftee tecMtm, the Hill slope 7 was feand to be
3.7, d
the SO% respenae was foamd witb 20% of ft racqnars 6oiog ffoe. 7'6en, ft eurve
of
Fiqnstiea 5 was lineetixad by Rta6ning 9ta slope and 50% sespoaac datapoint of
20%
aoceprors fsae. 8xtending this new cwroo mvealad an iftriocdon with 0% eFfea
(>m
relaxatioaa) at a frce roceptar rado of appmximataly 03, hodicating tlxt 70%
of the
rece,qLm would be blocked at ft point whue the ST nespmw ataitod to decay. To
deeermiaa a thnshoid fo: the more tantaronly uaed 7W peasupaeat. a cotrelatinn
bdween ST and TQF was ecashvcftd based aa eqoivaleet measiaemeats betwun thc
ST aird TOF namrmumts and a psdado-oocupancy af appraximately 5096 was famd
to 6etbcthreehotd
[6 M Bnitding the Moddaot
I096!] As thene is Senmally smns d;ffetooee betwoea du inftiid model of tke
process
and tlro trua model, there an be some ccmr iaitially and suuess of the
cantrolkr will be
defiaed by how quiddy the model can be adjnated to sanOCh the tme madei. Rapid
a4aetmettt can be acnieved by teplsoemmi of the migiasl rnoael's paramelm with
moaa rcpmscntative onas fcom a:aodetset. wham "modelseC nefiets to a mattitOda
of sea
of patannews detannined for nlAoed and solevant proass models. 'dlu inodelset
compriset a gmW of liloe-represeotation pnecesaes, similar in mathematical
consftuot
2S but diffcieot in paramaen of the orodel.
[Q070] In ane embadimmt, the made]set can be built by repeating the atepa
dexxibed
balow and as gmphad in an axample in Fipn 3(miaor steps not sDown). ft a
awltitude
of subjecx ptoaessea. These a6aps can iocbdo:
1. A ecandwd Input is giivan to a moltitade of subjecc procesaes and tlu
:aspoate
rxauded lUO. Tbe iapul is chosca.based on ft expecoed rangn of eesponse and
the
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qnalities of the inpqtls. For deng admiaisuaeioa saonatiOn is dssired bat not
tosicity. An
cxcmPhr9 dase is the 2 x EID 95 dose.
2. A detasot of muchod ootp~R amd Wme dstapojns is ssaembkd fs+um 00 aosraan
asd
stioo-satroted poiate, and adjnsed fo: oosHocuidw 101. Soma zao valae tespwsa
S poums may be added at tudns tmua to facu the cgdmudm to rets to zero as
waobd
happen oaoe the Myg is caasp&etely eltadmaNd.
3. The dssaaat may be adjusted for nonvmhasy io,pubs. ior dcug adeniaiehaaon.
tbe
datow oould be scaled by i6e cstio of the 2 x ED 99 dase to the dose givea.
4. An estinsadoa of the oodk~ ior thO paraQmtess of ffie governieg eqnaticas
of the
10 model of reepnmse is caL,vlatie& ta oee anbodimem, the nesponse is in terms
of
~o oewp~cY and/or tbe nonllnamities have otha:wise beaa inoospozated. 1be
oatimatim can be doee using a reenca9vws aonlinear eelimabon on a Z7qrlor
nxpsadom of
11s: awAaTs defmiag cguatiom.
5. Fnll time-owusta for the ioput according to its pvwafng aWstims em be
geaesMd
15 102_ Fa each model, the model's esdaamed pammumes aos maated into tDe
eqaadon sad
impulse veopomses ane calculated for aresum" auwuat of lima, psefaabiY tmrtil
the
modelad iespome falls below a levd ooosidaed to be o 11 p.
6. Shw]d the modd nwe ps[ame6css t1w can be opdmire4 opamal PaammaR ae
foaad. For the Lagueae model, t6e oQtina[ Laguea+a pok for ach nspoasa can be
fooad neiog the ea6aulmd impuise tespunss dama and an isenfive ~ ovrr tha ihll
.mp of Pmdble Poin=
7. Shnald the model be a IAguene or other similar slate sp ce mOdeL mo&Aiag of
the
fii6a ga+as for eacb piaoess' modeled impnlse mspoase om be dope 103. This can
be
dooa asiog a lnst squuea astimsffion of tbe paramoLets (here, the pnamebess
can maltm
op the outpnt gain mottix, C) of Sqeatios 1. as:
c, _~~ aTg (6) 1
wbera E. is s mahix of Iha state vecmm x, eaiauhmd usisa A aad B anatdm and
compiled mE
a=[xotxjI ...xRlaadX'[yoY, =--Ys~]T (6a)
a vactos of ineasured rospauees.
S. An aretage model cm be oseted by modeling 16e aVerap of all the Msponses.
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lWyl! Conmuon to a model fortnas with the optiaoal steps of 6 aad 7 in this
embodimeat is advaatageans. The tnodel could remain an impulse nesptmse
however
there is rypioally Weater cmnputMm recluuad baeed oa ft siu of the vactots
involved.
Responses to hnpulsa dosing of r0uuonium were foand to be oo ft oidef of lU00
dmostoM which would be ustwield.y in applieation of adaptauon techniques. In
one
embodimeat the modalset is eompaed of impulse mFones tosnWictad fiont previats
uses of ft control system. In ft case of dtug adndnisaetion. thn previaus
casrs can be
gatheced in procliatcal niak of the eOnti~ollet. Ottur tommonly usad model
fmmats fvr
which parmnasdts could be geaarated and storad for reference iachxe
aatoaegtessive
mndels (ARMA. ARMAX and Brnt-Jeakins models, for example). ttmsfer [nections
and zaro-pole modeJs.
[09721 As the orattroller is used with tm0ae procr9sea and to tespomses to tho
iaput(s)
are modelled and recerdetl, fie nronber of proeesses in gnbgroups
(mhpopnlaaoas)
baseQ on s6ated c6e:aceistica will gmw. For eaample in medical applicaioas.
Pabesaffi
oao be ctassified (groupr.d) aeoordfng to demogtaptuca (am aex, heigiu,
waigbt, tace.
...) and healdt canditions (such as liver, ladeey and heart failme). As the
namber of
padatts in a sabgtoup becotnes sizrable, a atatietvcally maaningfut avarage
response cmn
be calcnlated or othetwise detssatined for ft proeesses a[ihia that svbroap.
Tlts
sobgrovp avetaga tnOdel am thm be usod insttad of the overall poptilation aven-
ge
2o nespmse etodet as the ioitlal model (ttte mer would facilitate this by
enterin6 patieat
data pcior to the prooadme t0 elassify tlie process). This gtouping can thos
be aecd to
roduoa vsriance Detween the itdtid sttodel and the aatW proeess by usit* a
a*goup
nespooae model that shoold beer nmote tssemblanoe to the trtu tespaose. IU
atxurottlation of icepmses nd the davelopanmt of the wthgroups and sabecoap
otodels
is a metfmd of contiaaal improvomaut of the cattrol systan and a awthod of
oaduehtg
the variation in each of tlxse gtoapa T'his ptocess wn be seee in Figunss 6
ead 7. where
Aigace 6 denacuntraaes an exemplaty gaeeralized laocedure and Figate 7 shows
an
exenplary proceas cviQs use of subgrmps_ In one anbodiment. inapalso response
models
ata nowstraated panugh the u9e of the conw systern aad ft modeleet is
increased in
sia by adding m4ta impulse iosponsea to the tnodelset as tfie nsaponsas ans
gat6ered.
[00731 m a tutthwr embodirnent, chatadaisdc data relnted to the pcuoesaes is
gatlmte3,
staed, and used for tlte patposa of ctastlflcstion and grouping of die prneesc
toodels
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17
[U0T2) ia a faud= emhodhmeat. chataeoeoadc data related to the pQOasses
aSatheced.
stoied. and owd for ft pmpoee of classification and St+onpaag of ihe psooeas
mode3s
isft nlated subgoaps. in otx embodimem ft atcnwge is in the form of a dambase,
telomicmal or oHxrwtae, with cr without tbe model eocffmm vahua. For aatomated
drug
S adnainistratioa, the data gadwmd cao lnclada demogtap* data oxh as ask eax,
wei0t.
height, leam body mms, body meaa iodm eoial, ganetic md adhetwfsa. The dam
gmdmrad tat also ittelade dats nlated to lifestyle st" as smaiing status. 'Lie
dets
gathered eaa fmeher mciode oformadw aClated to healm eeadlROaa sttcb as Sdduey
fuocaioa. moan arterial blood pRasam kypatemioa aed di~bebes.
pW731 Ia oae imtmce ft ooeff cieuts of Iho idtiai model am aa avetap. meaa,
mode
or o&erw3se eompaled s;et of coefficiem consunetad fran the availabk
fiistorical do1a
fimn pttor aee of ft eesttvlla. la anotltee insaooe,lba caefScienb of the
inidal madel
are an avaage, meaa, mode aw atherniso ooanpiad sac of ooefficleate of a
sabgoap of
the availeble oW of awdel cociftiem seteeted aeoeedbtg to thared
clrataduietics.
aS Should fmqtt petfannanae be desitod. the inidal model ae be ebo~ea to be a
model of
lawer respamse rdaLiva to ft madele tEat wonid odLeaim be selected in tbe
previoua
two me<anexa. 'lms wiif cause ft eeorodla to defiver more mpat to reacb ft
wtpoint
aod wM dreeeby on avetap get tn it faaoer. Alomadvaly sAwld safety be tfie
most
impmtmt ctitetie and ovatsltoota in zeapme undeslta6be, the model coefficieeas
caa be
adeeoed tb be aee that vuanid 6ave a higbet respOasa.
L007s1 in oae embodimena, pnoceaees for which the syonem (coono3tar, adMsor ar
od,o:
tmtanintion) Las aheady bten aaod cmt ose tbo ienpmiso respcose andlaR
ooefficwts
calatlaDed at tEe previous use of the sysaem, aa [be iiritia! modoL Por
e.xample. a pamient
tCutniag fot a fedlow-up paucaduro eaa use tLe mode! data fiLO their pevinus
ptocedae. As intrupaim variahft does oeour thaie is a chance that @x patieat's
taspone may have ciavpd and ffieicFon adaptatiam from ft aigiaal model may
stitl
be desh+ed. An example of this Is the devatopmeat aod/or pioecesaon of Iddoey
disease
re3ocing drug cleacance and thaeby euoxd'ina effect
[A07Sj in snothee embodimmt, a cxetegl dataset eafs-, and si the end of the
cootrol
proeeduass, paocese model aad chanctetietic data is smt to and oompoled within
the
m^dab-L 7Ws central dauaet may be cantral to the cagadmdoa in wfdclt 1he
syatem ia
being aod. saeb as ut a hospital, at may be eefltral to political asganisauame
such as
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1g
[0077! Modal Adsptafion
[9478] Based upon tha teepoaae(s) saan to the iaW giveo. adaptatioo of the,
modcl
perameoees is performd to iuoppvve the model. mske it more eFoazly Ksemble the
specilic pmcass, and thexeby improve tbz esor petformance by calculaft and
administaiag mame aavtaoe inputs. As !be process is oot compleely lmawa to the
oamputer on tbok s,st taatiag, the m0ae1 for the paaent reimrae to urc drng
beiag
adviaed opoa or controried can only be gOCSsed at As a best esdmate the
nspon9e Is aet
to the popaladon aoetage respoese. This IHroly will eal be the coaroct modal
but
1o assomiag a noxmal disaibnticn of responses, it wi111ie dose enoagh.
/4daptaaon of tLe
model cam be peaformd to tednoe error dne to nrisrneacb. 'IU system of this
woAc
inpoves upon the olode! in two ways: model swapping and recunive estitnatYon.
[9079] Mndel Saapping
[0080] As a mle-of-Wwnb far sasae wboffluma. adspmtioa is c.apable of bandting
padait model parameoer vaeiatton of about 309k ModeL swapping - ssbstiteLiOa
of
anaQher modePs parartn:tas for the cvzjcat model - cnn provide gtvss tuning to
tedLtoe
ihe wnor in the caodef panamoers to bevnla msugoable by adsptaam As fnquenR
awdd
snrapping cao lead to instability. it is typically only drnie a limited nnmber
of tiea3, end
ps'efaably modet swapping is oaly dme cmoe. With a sn6aMtiql enomgh mcdelaat,
one
swap can be aufficieat.to eossme stability and impsuve earor potfnnnuce to tba
poieK of
agcqgawily.
[0081] As as aa example of tlda. NI~O drag is given tD a patieet smdagoing a
prooedtm
tequ'uiq paretysis, As the operation ptoceeds, dats is gatba+ed for die lavel
of blogkade
aeeo (tha oarput~ drug giveo (the iapat) and the modeled Qstient ocI y level.
Alftr
an appaopaiete number of ioenrioas of patient tdmnlam bbuluade measure, and
drug level
adjustraent, the ctprant model is compared to the ottror models wiibia the
pattent's
a&gto0p (or in the ovcrafl popolatioa abmld Ihe nnmbers of peviously messuted
paumn falling iam die subgroup not be gne eaoagh). Ca)cv]atiaae are made for
what
3D reepoass vroald be had (what level of blockade w0uld be seen) whh Ihe drng
iepuef
given. fnr models having the parameters of Me other patieet modds. A best
model is
chosea based nn least enm and tbe eutmnt madel (subgaup or popubti- rnean)
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19
msponse wonld be had (what tevel of blackade avouid be seen) with tbe drag
iaputa
given, for modols havnxgg dro ooefficient of the atber pstient models. A bea
model is
cbeaen based an lmst caor aad the eodfici t of the canaet model (sabgxoap or
popalatiau smeao) are replaoed by tbe ooeff'ie;ents of tbe best mtebimg pdv-
seooeded
indiridaal model based upon the cbsat matrhiag cakadatad responee. ShauW 1bn
iaioal model psove to be tbe most t^epaeseatative, abatUntion is not teqnimd.
L0o811 Ia ame emboffimeat modei awapp}ng ndes psaoe afta a pre4W*amdmed
oaQnber
of duapoinls wbae ihat number would be sofflCleat oqgh to ellow an apprapoata
dscisroa to ba aaada.lLis cau be thioa6b a ru6o-of-Lwnb appsoacb of ailawing
acattai:n
munbea of datapciats per model pmeseot ia de mcdelset, e.g. two ffmwmem
requiaed
per atodd in the modelsat. In ancdm embodinoent, nsodd swapping taka pLm after
ao
cvrat Fmr dmg admimisnatom4 shis eveat cwa be after a catain number of dosee
or an
asavai at a a.etam lavel of fmwt9n or atirr a pme-deeSned amo t of thne bas
passed.
iM] In amdmr easbodimaot. sarappdmg takes pdace If the arn~ seasas thet the
19 modal is au cieatly 3nooerecx.
[M] In a atLer emboQimau, tbe urer fmzea ewappeng to take placx. This may be
becs,u e tbay feel the modrd is nmepaasentative.
WW] 1e anolher embod'inseat tbrre aue precanums and eavt coeactlao in place to
ensure that the afodel ceefficieata am not swapped tac coefficients tlmt ace
less
iepzeseatadre of the cvtceot prooess. Sme ecampfaa of poss+'bic acdas ane:
pafonming
the nmodelHng as meded - e.g. no model swappft ii tse model pammemm an wimia
20% of tbs model slaeted witb at the timo of mndd swapping; e>thWing
poouroatlY
imcociaal models Svtn the modelset - e.g. should the pmcess look Klce it
ieapeeds at a
degzee highar tlmn aveeaga, do aot allow madel swappiog to amodd Bret respoads
to a
degioo lower tbaa avataga; and tajectiug the model sslticted in t1,e model
saapping
psoceas if it Is a clesr misrate - e.g. a process respoodieg as a high
nspondar shoald nort
be mpleeed with a low mspondfmg model.
IAOBS] Model Adaprtatioa Thaovgb RecaYSlve Ssdmaliou
L06861 Once the nudsl moaeling is completad. RLSE cm be used to update tbe
pwcbss
ooefficiou (e.g the gam and C>~tri~t fns models of the Yo at of Eqaation 1) as
aaw
iafosmatiao in u~ma of oatpnt and praeess staoe aae received. RISB cxai be
performed
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e(t + l) = 3-(t+ i) - LY (t } 1)C"(t) (7)
0(t) t)L(t + 1) t)
c(f+l) _ +A+ LT(t P(!)Lt+1)
P(! f 1) - 1 ( P(t) - P(t)L(t + 1)Lr(t + 1)P(t)` + 87 - YP(t~
J A+LT(t+1)P(t)L(t+1)J
wbate tlcw me nqaations for erroc: e(t+1); ft new puanew uyaate C(t+lk aad for
the armroovatiance mstrix: P(t+1).
S IU08g1 The EPRA pacameoas can be modifmd as the oau prog>uSes to iefieet a
bettu
uRden;gan[bng of the paoent. '!be fotgetdng factor, A, can be incremed from
its stactiag
vaJna to cetain moau inforntatien beliaved to be mane nelia6le (.e.
rcpmsentative of the
pomeoia1ly dmgmg pstient). For axamplF, the fargettinig faetor ears be
itecreasod 6raa
0.95 oe 1_a As well, the paeanlettas ¾ and 7 cmt be resG to zeta~ as paramtas
P aad v
10 are not deained once the forgao0ing ia tnrtrod off (at ). s 1.0). 11ds
updesa can occnr when
a omtsin nnmber of doaes have baan girea or when a cxttein number of
ineasutsmcots of
respoose have beea reaonW. Also, ft parameters cao be modified acemdmg to
facoarta
browa to atfeot iespoase to the drug belsg advised upon. eoob as tatperatura
and the
p, eegncs of eeha dnegs, to redaoe tbe forgatieg in times of gretar cm=let.y
and
15 iacaeaae dw forBttiag when these facKors have a geeater fnflnenoe (Cm ordec
to mdnwn
fast adaQtadon), aucb as wheo thnre is safrioiatt volsailc aaesthedc oo af[act
the NMB.
R1S8 is deaire6le at all times (ev- befbre the mtmdeling point at whidh modds
are
sadeehed and adaptadoa potma8y lost) to avoid situations of uader-acnmiat
where
tno little iopat is givea to ovaoome ft threagold. 7Lis oan bapperi if soo
little drng is
20 givrott and thea the systom is umabla to Set dsta for ns+nodeling, ss can
haPPm with low
respoaaers. tbe systern can then be stndc waitin; for the model to eeared
iteelf and
evenptally ihe uee may haVe to ioGervrne_
[AMj Pw tbe bcnaf't of other calwhuious such as daectntnetiett of rmmn{ng Qtug
in
the puient and ft cslcalation of infusion m9ea, an impafae tesponse
represartatiae of
tho petia-t's drug flow can be niaintaiaed as welL If a differeat ioodel
format is naed, ft
impilc nmpmse may taftd to be updatod as wdi. Dua to the Wmly laW sise of 1M
veotoss nsed, snhaion of F.quatioau 6 imd 9 aN be impxsedcal. 'Ihus, tho otlxr
facmat
caa be ueed in a manner similar to givhtg an iff4)plse to a stats space model
and
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wedm naed, solutiaa of F,quetioas 6 md 8.aill be msprac~Cal. Thus. the omer
tcstmt
can be med ia a manner aiUilar oo giving an iwpniee to a smte spaoe model and
eyalaating npcaoAy aua! tLe taeponee has decayed below s leval canafidrled the
tluaLold for noise.
5[08i91 As deaicabte iSSUMM0na. DOWASSIS ai the moQel WWMM paooedme sae
rloown in Figme 6 for a PoII datasa aad in F'igma 7[or a model adWWWn psooed=
ia
qrluch eabg<oups ats use& At tine am 110 of ft pmedoxe the piooees model
begias as
the global avetage. Data collection 1 t I of tasponse, model stalc aud inpoCs
givan etatts
and cominues as luaa as the eyetem 98 in usa. After each tienestep. conditions
are
chedEed to sea if it is tirme far a model swrp. SLep 112 compKes ft number of
ddapaiats awmmdated agaiaet s psedeteQOOiaed desired amoM aad oeKx lt is
teaclYed
the awdel awap adws plaoe at step 113. After the model swapr RI.SE adapwtloa
of the
model 114 is perlo ed tntH Ota and of t>te case 115 is reached. Unce the end
of ft
case ] 15 has txea reaebed, abodag of ft model abd pweeac chasotetisties is
perfornmed
116. Sumge eao be in a dssahaee, ieletianl or otherwise.
I80907 For tbe pioosdune in which sabgaaap am aaed, the paoeedme can surt 120
witb
ahe model aade6am ea. In srop 121 the wes emms dats mlating Wchamcftfixfi= of
t1w
cument ~oee1 .l9m data is thea used ao identify a snbd+toup of ptneaaee
simtla< to the
autent ptooass based upon the irOxaed paoecse duacurWc deta. A+eodel can be
oomp3led from this snbgraups ieadds dbsi may er may nat be an averW of this
model.sat wbgmR 'lU caee tlten pavoeeds os it did for the pm.iovs deaceibsd
natantlation with dma e011ection 122 of tzzpunaa, mOdel stae and iaputs givea
a
doCisioa on Laving enough dua podnts to mabe a model swap 123 fcUw+rod by
rnodel
swapling ffi nep 124 if eamgh have bem collected; BLSE adaptadon of the model
125
until the eod of ft csse 126; and eeoring of ft model and proom
charecteristies 1=27.
"11 EXCMPla1r lnimadadow
(IBQ92l 1mpJtm=A=on of Adviaoiy sya6eau. In one im0amateo, ft metbods of
axouneag for nonllaarixies and adaptleg fos proceas vatianoe are lnootpasated
into an
adviso.y syatem fcr lLrias iapata inditady thtough an mftmmisty neer. An
examle
of this is an a6viscay system for drnY adminisP'n, which can maloe dosing
resaamwodrlioas - how much and when - to the ueer haeed on measured pat9mt
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an atabulawty dovice. The initial dose is dotetmiaod by tttanufacdner's
iecrntmteadetima or aa appmpriate dose for tha p tieat's populatiott subg:nwp.
[00901 ~~~~~ w adopt to the individual's response to the dmg.
As nse ptooeeds the adrisrny system laaua the teapoasc for eactdi pstimt and
is bettw
able to predict @te optimum dose desire8. At al ] times the utw can have the
tinsi say on
what is given, maidng this a very safe devico to use in a dituoai setting es
sIl atlvioa will
be questioned. and backed or rejected based on madical experie,nce.
[g09S] A block maWstn of 1o advisory syatem for admioiatration of dntgs
appears in
Figm+e 4, as it waold be inompolatod inm a nodWe rcuLined inside a patim
nwniDor 47.
'lbe patiesR tno>ntor 47 is firctet cornpeised of aeasieg andales wilh pnwesng
49.
display Sl, a databos 50 to isoa+cotmect the sebcomponeats amd poss-biy other
advisory
systean moduks. A{so in the system ate tie paticot I and the heahh
ptofeasional uaet(s)
58. 'iUe patieat tnonita 47 mtsracts with tix patient 1, sending etimu6 to
egdt nspmae
if aeoeasary (patdwe senraas sncb as tbe BOG do not do this) and reaeiving
response
data fos pioceasfng and diRlay to the tscr 58. Zhe ffier 58 gives drug to the
patient 1.
and iuEormation on drng adnninistated (slfoold qrote be tto atttornattc
feadback of tttis
data), and paae.nt and case details to the patient mouitor 47.
10096] Ybe advisoty system 48 receives data on dtug given from osa 59 aad
trsponae
data fcuae sooeing arodalo 49 via databus 50 and staes the deta in the input
and respaom
2D records S7- The advisory sysoem elso tecaiva dau oe fLe pavant and cass
pararneteta to
aid selectioo of m. inroal mmheanatical tnodel of tha patIa-t ttaponse 54 fivm
tme
modelsa 53 and fot use by the otlw ptooedtaes. Othea piacedures ityAude
atgatith-
for mdeptadan of the atodel 54 to bemec stut the petient. for estimating
utttt:nt dntg
lerels snd response 55, paAietion of fnnue dtvg levels, responses aad time to
thoee
levels and respntgses 56, and gmmtioo of advi0t 57. Finally advioe troo advioe
gewtmor 57 is pat:sattnl to the patfettt mwaitor via databns 50 ifsr display
to the nser 58.
[0g97] A vetsion of a aer iatetfaoe for the advieoay sysftta vaed for the
admioisuetioa
of Ni-18 dtugs appears in Figiao 5. Inputa arc on the lefl band side of the
scroon with
Iwspital ?,40, paOcmt 241 aed ease telated data 242 at tlo top, snd evmt iopnt
244 at ths
bottom. Oatputs are on the riglu hand sida, with MNH mewmmnim data 247 at top
(strAs vatisbies. raw and cl>atted 8ara below thet); estintated dtog leve1249
inforroation
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(status vambim iaw d ehslted dssa below thac); darmated dree level 249
fafnsmatiae
has-ed below tiut: md predietie s 252 muil 16e .esponee ~dmn to the level of
ffia
user's 1mdwted satpwdra, t6e kvel of [amatioo rowmng and until ievarsrL
[009'7] 7ha mer ioted'aee dispayed was used ie eliuieal Gomg of the )!U-+IB
Advisoty
Systemt, md is an eagfneaiqg prototype. Ii ia prmootnd heae for mqAammory
purposes.
Pawre vefsiona of Hris ingMadAtion of tbc 0yaWZ1s, methade, ete, heeda eao
luva a aeer
interfaee mate oq;amud to tha woctflow of dfe phyai¾lan using the device,
podaibly
w3tb data display and iaput; ocgaaixed aeeotding to lbnctim for example as
patioat
deta, sensor ontpa[ md hudwete semtp. The mr mtesfa<x of Fipm 5 was daplayed
an
a lnpeoy cosopota and, w&h NMBAS iaeorporation as soflarat inoo a~t monitor.
wonld hloely be dunged tor oamgmity with tLe oaar iaterface of the monioor as
a whole.
Sisulwiy, if the systems. niehoda, ete., haein aee made as standelaoe units or
otherwbe
adapted for a vaa project, iocgnd;ng n4a-d~uB'moa~otia8 Pmjectis. the display
woauld
mm blety change to refleec wakflow and sixe remncdow.
(0169] 7be advfsoty syaa;m can socaive as ovet piior to tbo sase: unique
fdeatifters of
the pstieot, thes psocedtue md the hospital; Parieat (e.g.. ooaoprIaiog age,
sex. hmgta,
weigLt uid -) demopaphiCS md heeft conditions (e.g, oanguising major apn
padmiogies and televam d+meases); details of the cate siding apmadoa of tlu
advisor
incmding pmduied aee-leatph to ps+ovida an en dpuhn so tlnt predletloes of
amrnmts of
dnig eceded to asrive ae tUe deahdd eetp" at the ead of We case oan 6e mas~
tle
desbcd dme between doses to set tlbe leaser amoom of omo bet,veea doses or
adjoa~atta of the infaaiun rata to avoid ccat:anal e4asetteza amd abofidunfim
of
amall a oams; md otlw pettiimot data. In oaa embodimeot +vit6 idaeaae oo
Irignre 5,
the advismy system raeeivea as iapnta floaa the wee(s) daring the caee: de" of
cHaiCally impOrtaet aveflts 244 sueh as the amount of drag admiaitomed md wben
h vrae
administeted and eveata mpoatant for ieoomd keepiW oorswhooe to t'ha model 245
stradd tbe oompnoa's modal of the patiesd be appaceady flawed (e.g. indication
of
saspacoed overdose or uades+do e conditiaos); and o9u$e.
[0101] In ona embod'uoent, ttrcoughout the case the adrisiuy systma cm pQeaeat
outptft
oo tFne aesr aecLming for example: dqail6 of mammmosts 247; mmfts since
indtbacmg
dose 248; atimemes 249 of ahe cuumn md historical iavels of drug in the patimt
aod
couespeciding est.imeoss of respome to those appiwdmrted levela as auraeical
aud/az
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and other relevaat dtuga: advice 251 for dosea to atrive at the desired
>esponse In the
deaited tsma 6etveen dosm and at the predicted esd-of-casa would be displayed
as well
as seoottmended infusion ratea; emrnarod timc to de.siied endpoiats 252:
sensor statns
265; aptipnteot status 267 and tr>+asasiasion inoetval 243. Also shown is
tetnodel iapnt
246 which can be used to force a ttmodslipg=
[01103] In saother ittateatiatiao of aa advisory system, the advisory system
can inform
the uuer oat the le,rtgth of ti>tx onb7 rndicomd tt~se levels are teiached Far
example,
with am NMS advisory sysoem it may be desieed to know whea dw tesponse vtill
tecaver
to a desi<+ed ieveF (ag. TOF of 10%), when the patient can bmathe
opooteneously
(judged to be a TOF of 70%). and when the pstiaent can be oonstdemd revetsed
(a TOP
of 10U96.) AnalogOUS eodpoina for otLer drngs swouM be tlte leugt6 of time
mntil a
desircd tesponos is seea. unttl tho drog is no kmger effaetive and ant.7 the
dtug is
elinAnmmd from the petiem compkteJy.
[0163] The time to these eveats can be deunWnd by s.dvancing the modd in titne
uatil
dw level of dtug falla eaou$t that the toapoaaa desited is reached. 1ba
tttonber of
titnesteps desaed to do so eonvatcd to nnits of time is the ansaar.
Calcalatioas are
perfonned fae the model, modifiod for ao-inpw ooadiaroms:
;;ft=}Ij = .~Lr~llfQn: a1=rt~
y{f) = Ci` x~!j ~c,
7bis Is perfomecd iseraivdy while itxteasing t6ne t mtt7 the dashed level is
trached ar
until the mximum time horizon of oonceto (this is needed to pmvent in5oite
ca[cnlaaon) is wroooded
[0104] 'Chos, the systean, mahods, etc., heaeia cea saw a watning systaai sd
slatm,
to watn of impead=tng evem aad to akut the nter if events ats posstbk. An
exampls of
the asefitlt-esa of this is dw clinieat applieatioa of an advisay system for
NMB dtugs.
Wateiag of itnpendieg tstum to a levael at which the patient caD nmove aIIows
the
al0andiag oser to ympaie and admiaister atm, e HIV1B dtug, psoveating tfiat
motmm.
reducing risk of injoty to tlx patient aad allaving the surgery to ptooeed mou
sttx>oft.
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SiunOarly if the pafienc ia aapablo of motioa aad the adv99or eicber semm this
or ptedicts
it with its madelft fm+etion. the attadiog trsa caa be -len and act
accadingly.
[OlOS] An eaimaoc of the aatooet of iapo temeittiag is secalwlated eadt
tirxetep, aw a
de.sired m ber of c+mesteM to keep up with impoloe tetponae aJxanza doe to
toodel
5 adapmooa and tbe dJmbnshiug etyiects of the inpats ae dm piooeeda. Aa
memplaty
amdwd ia a somoM of the cootokam of Ux iapule mpoaae with the iepat hismry
vxtor ovar a mceaR period of titue eqaivaieat to tLe tuno-teo6t6 of aLe
impnlse iospoaee.
Foe eocample, ooaatdec a pafim whose ho~se pppoaae laeta 300 tinmea9eps, aad
avbo
has receivod dtog at timesoep 0 and 200. At tlmos" 350 this pdicat aill
subsmada[ly
10 have no rimmuft drog doe to the fuet dose md wM have t+twritdog dtng becne
of
tlre second dose paeponiooal to ahe atoa mde~ 60 cnr+rc of 60 impulae response
betweea ielmdve timestep 130 (Erom ctt<nea[ tuaestep: 350, aubtractiBg the
tuaastiep of
adminbkwm: 200) md the ead of t6e impalse recpoure.
1O106] In oae embaditnmt, the advisory tyeteta prediats ahat Ote fmare iopu4o
snch as
15 Arog inputs. ahoold be to atriva at the do6ed levels of tetpoure. In oaz
ioWmflation, an
extmded horizan pndmve eoogtla is aWied to daive the iupnt tepcated es,ch
toF etPg tbat ar01 aaive at t):e deobod eefp,o8nt at a desined time, N aomber
of timesseps,
into the futaca Stmti eg fiom the hitial abe0e ecpatiam, tswmieg a eoastaot
iapax smd
estitapolatiag iM tM f6teme-
z(t + 1) a A x(E) + B a(t)
=(++2) - Ax(r+1)+Be(t+1)aA(As(t)+Bti(t)1+Btt(!+1)
~ A's(t) +(ABie(a)+B)n(t.)
(9)
~(tf =Y} a A~ s(t)+Ssl~-~+A~`=+...+I1Bn (10)
aha+a tbe seeond eqaatiou waa asrived at by mdmdbdng the fuat eqeaoioa for x(t
+ 1).
The tiebe+e response wiH be yR a Cr x(t +N) and the cm-at seaponae is y(t) =
CT x(t)
x(t). The iaput desired to gat fiom ffie pffesem sls6e to ahe fotnro etate cm
be [otmd by
subhwft the two ftsponm and dm solving for u:
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_ ('?(_4'~ ~(/t+;.~~ ~+_l\ ~+ ..+IIB~itfl rtlli l
,Ultl _ f'T A`4 - j),ritl
~t L (_i' - +a } +IJ ~ (11
For bolus-etyle, disaete inpttm, there me no otber inlwts beiweon this Input,
n(t), and 1ha
nacc pedicted dose and Equation 11 reduoes tt-.
(:. A.. 13 iLJ!
As eaCther etesnplaty auAbOd of ptedictsoa for a syaoem in whieb diExxm ieputs
ate
givea in an oYadeae and >ecoveiy feshion, die inoenal batvveen applicatiaa of
iaptua is
netasttad and recowmendeum aie iaa tspeated domes if tlae ia sefCuient drne
unW the
eed of ft caaa er tYactioeal mputs are detertnieed and cec=an>rnended based on
the: ratio
af sme teamiaing to the timc between atandacd doeea.
[O]071 In a sxood instasdat ae for catculating iataeion >soea. tha raee ir
oatsideeW as a
method of replaeemaR of drug lost over tlx timeatep. Drug cntnoved can be
found by
calcalating tfoe dtng remaining in tbe paQatt at eha curtent tit>n; and
suhttactmg what
diag cewAha ia the next timestep.
[MOM In a third inataetiadva, the iatusian ca0e is deterniirod by clasac
phatmnaaloBical
methods by using the expac[ed clesrance t'ateõ C!, aad the desired
eonmatrstion ia tde
plasma at aeady atate, Cpss:
wnJv.tton re:ic =C t: l.:M,y ~1~1~
M appNaCh t4a}r a02 be Pery nREM GUmide of the aYElage CaaE, ad ]t typicall~r
CmnlWt -
tolaate vatiation in padant pararoetus. The pbarmacokinetic terms bave to be
known
axactly and apeaif'ically to the patieat undergaing rhe ptooedms.
~II
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[0104] in a fowth imteatiatim infin9ao recamnendetions a- mede by caleolatiag
the
tepeated doaes needod for boaizene of iaamaoing aiza up to tlie dedrnd
eodpo9nt. and
tlten averagng to get the fiml ovemll valae recammenft& 7be dose at each
timeeoep is
calonlaced aoooadiqg to Hqpation 11. It is maftroadCally poaetble to have
aoBative
velnes depeadmg on tlee cketmsmum: wde as if the cm~at memunom is at a b[gher
reaponee 11un the desaed fulaie napoase. '1heu+efam anodw vwman of the svaap
dosing apprnech is a eonoftwaed vesao in wfiich only dro pomtive valnes ace
incloded
m the awage.
[0110] la the above ao ex0eaded ho~sm pQedtadve aonthaa scir,me was used.
Q11wr
eomtrol mebods ioclade for eatample aeaenalasd luedietive oamhol. miaimom
vatianca
and movi3g avorago alocbaetic conMOi. ~emt qurkaQc cmbol, self-trmiag conud md
VCkle PLaCCUWft COUtrOL
[0111] CAN>pi8 >biPi~ATION: A Ne.ormmsculer Bloclrade Advisory
SyAr.m (NMBAS) advieas aaatltisiolosiata on rocmmnmm deee magrdtade and timiog
for malntenanoe of MMB at surecally favnrable. yet eauly revfta'b1e levels. A
praepeative iendomimd, eeah+olled clieieet teLi was condatod to inwrostigte
NMBAS
sefety and ef6ecaveoeas, testing the hypodaes Ibet NMSAS is at leest es safe
as, and
pQ+ovide,s beuer cane aa oo paied to wemdiud pactice.
[011Z] A prospoenvei rmdomiud, oonaai[ed, eJinical aid was ooobjOad wit6 0= 73
P~ (ASA Rhysscal 3ti3ane IIII) m**Dft SbdOIDi09l lmpaey ander Benerd
menhak - 1..5 h with parOfeVaCelar bbdw* RBillg 7GlnropllpU. Padows WOIL
allocsted to ammdend Ceae or NMBAS-Snided tocus aftwountion_ Tu primary
OYLCOIDC Y6l" qleS dt6lpCidcuOp of mueoperative OVOpl3 ROCCtlRg imWig-w Nbo.
ScOOndmy 0o20o01e vadables iacLoded Oraie-440W (70F) mioa a1 rovensl nd
elClY"m; the tOtd d06Ci of amodpal. tCVE[8W ApMm aumhotlm and OQ~w drugs;
the foctde¾ce of poa6opeatlve adverse eveam. aod the ia¾idesae of
amesdbesiolosi'9t
non-oomplianix with NMBAS recounnindations.
[0113] Of 73 ee:olkd patieata, n= 30 per group avere eftNe for saalyais.
Patient
de-orVbos ware eomrmabfe betwees tbe groopL 7Ue ine9deaoa m totai
mtreopesatire ovem aswcieted with lmdequm NMS was WgngkaWy lower in the
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NMBAS gtoap tompaned to standatd tare (gl30 vs. 19/30; pc 0.01). Mean 70F
ratioa
priw to revasal wwo higher ia the NMBAS grvop.
101141 C,ompared to standard prectice. ]YAEA9 guided care was aseociatcd widt
improved NMB qaality snd h3gba TOP reaos at estabatioo, pobapially rodocing ta
tisk ofneaidnal NM9 and improving palaperatirepaimot safety.
(0II15] Cloeed-toop Cotnrd systems
101161 In anotbar instantiation of the invention. the techniqm taught are
ietcgratc.d into
a cloaed-l0og control eyscem. Opeation catf be simiiar to the adv ory syateme
described
except the inpwa are giveu directly to the paieft. Thie syetam cauld be much
like otlac
elosed-toop oontrolleis wit6 foodbaek of ineawued tapo se exoapt the modetiog
Prooeeeue wonld follow the descn'bed appoacH od model swapping fzom a
mndelset.
artd with aondnuous updeoe of tRe parameEers through estimation rectnoiqaes.
As wel1.
nonlbtcaMas of 8ie pruceaees dmt this is appHed to cart be iooorpmaeed into
the amdels
of tbe modelsa.
[0117j Btoodfrx Determiaatioa of Ihug Catceafttions
101181 Blood sauVling is nonn0lty desiczd for detcrminiog du ooneentration of
drug
ageul, aitha NMB dmg or otiwwim in the blood and odia liteaes w6ea parhormiag
pbemaooirinetic modeling. '1'his eaa be daee when the maolt is not needed
irnnxdiatefy.
Ie an opaesdag roam where entometed ooubul is to be used, tht dme desirod to
get tbe
blood eample, auallrze it and teport its valae, not to meutlon the asenpowrcr
and rnweey.
is m available. Tdis ia especially uue with the cbangiing attsre of the
patieat eendit9oo
end the fesw kinetics of some dntgs.
I01I4] 1n anoaher 0epeot of the inrantloa. instammreona drug eaneWAMtiCFn ie
approximated without blood sampling by eelatiag responu measured to mpnts
given
rhrnugh a ovntiauany updated model. W9th knowledge of the cnlaationahip baweea
tho
reaQoaee and reoeptos oeaupancy, transFation b"een the two can take place. As
well.
e:nce,he blood co0ocnnnoon can be related to raceptor occupancy .vitl<ia the
appiicable
rsaQe up until fon oaupancy. blood camcouwbm of arugs can be apptoaimated by
ma
meaeofed eosponee.'11fie ie advantageous es it elirnioetea the need for blood
eampling.
ADMlIDED SHSBT
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PC604-732-1601 T/~o07/001605
17 Fabruary 2009 17-02-2009
29
r@!ZO) To cmPbWze this procas in the teama of pbwuucolhetic (body etPa,-t on
the
drug) and ph-mecodyaemie (dma etfect on tbe body) modelling, as blood lavds
aro not
available. inaigbt into 15e orgaoieso-dtug system is ttuough the raasaa oulpat
T3ta
paieat model is a ph~nucokbmde model appmxunatalg oopceafiatioms of ihe deog
fa
S the peimL Tbie modei is adapLed to refioct wlut is eoea m 1he
phaonacadimuaies, the
mqmm measored by the aeasora. 7gus, an atsaaoe of the blood levda can be had
based on the measaeed neqonee.
ro~] Pio"ou of ttoms Pcoblem
[01221 The sespoase nmnmnvd and im conesponding ntodei may vatq wibsewdiany
fivm
the atlfa modefa in the overall gmup or uftroap a ae]ectad by peeoeta
sharaarristics.
As well. the nspom aad coattapOndiog model may be similar ammb to othri models
of proixases eem that bad known peoblema. 11wti in anotber atpxt.lbe proaesa
cmedcl
that is nveakd throaah adapbiao, in asc of the ovnno8er or adriaor or otba
syatem
iacapoeating these meftda, can be aaad to paedict the stapu a4d ao>xjdna of
tbe
prroaess nadrr ttot.
I9133J ta oae examp3e, a chnaical pQooess demoasnat>ng a slow rospmm may be in
need of mabdensum Once tha eoMeol syttwe - ig iv., tLis in 1he iespoeeo,
-, wmaodatioms caa be meda to the user that they mvesagaoe the caose aad
provide
PeNVE111dive n>ettaaAmce. As pa0eat beallb aa dlc7a~ t!u phatmscaitinetisa of
a Qmg
in the petieat, t6e inveerae aay also be ttae: menummout of tbo patiout respc
ee may
nevesi iufncrostion es to the heaiW ef tbe patieat and show cbmdficadm irft a
paA.ionlar
eabphton cluster. As an eaample of dids, baxd an ehe nwpom modeL poedicaons
can be.mada as to the smte of epecific cmatie s of haEfls aad anan puboksin
(a.&.
livtt fuactioa) ielatsd to ahe sapeots of phsrmaeabmfts (apsczption. distdbeum
tnetabolfaao aad escaetlon). is an exemplary ase of this, ap admnmd
sdminieaetor of
tor.'atooimn milft oaicx lbat the pa;faat bas au abaroomaily long eFimiastiou
of the droQ
iatative to t6e otLer mem6eis of the patiwd's sobg~. 7be antomated
admimse~ator oan
lheo iadceee to the osa t6ie fact aad eecommmd that t6e ; --* p m, andergo
teaRng for
Inboey aad liver fuaotioa. In ana4har exemplmy use of tlds. the cwnvoee may
slao r+eveal
infcamadan on the paaent'c heatdi: if the padezWs mponse is foaad to be
signi5cantty
sho:aer than the nnsal xespoose, ehia mig)M indicsoc tbea maoaboiisflo has
been made
AI4ELiDSD 8EM8T
CA 02665121 2009-03-16

RECU 11/03/2009 20:07 00223388995 PT4
03/11/2009 15:06 FAX 819 953 9538 CIPO / PCT OFFICE 1jh032/049
CA 02665121 2009-03-16
17 Feb 2009 11:15 604-732-1601 PCT/CA2007/001605
_ ~ . . _..-- ---- 17 H'ebraary 2009 17-02-2009
faster. The fasrar response could indicata thrymid issues, metaEolic disordeis
and
Potmowny coneem=
[Oit4) Fodxnme should the piaoess'a aesponsa be idantical. or aeaeiy. so. Do a
prticuler wbpopalsaion oespoase, die g mcess may be a candidate for ju3mng
t6at
5oftivoy and testing can be advised. For exatnple, if a patient witboat
previoys hemt
paxOb(enna whose tesponse nmmb-^ the respcrose of the heatt-failuro
subpopulation (and
thla snbpopeaation'a sqmes are sa6ssentielly different the noanttl
population). tldea
the patient may want to midergo testing for tbo pantfcnhr waditm.
10 I0125] Tasrns
(0126] All tesm uscd Ixrein. are nsed in accordnae with their ordinary
meanings
tutless the eonuxt or dd'midon cleetiy indWtea otberwiae. Also tmless eapassl7
iri'taatod othervviee, t6e use of "or" iacludes =laad" tasd vico-versa. Non-
limidtt$ terntg
me not m be constexd m limiting ualess axpseasly sfated, or the oontext
ciearly
.15 ittditxLes, otheewise (for exanRle. "ineludiag", "hsviag^ and congising"
typically
iodicato "iPoC1od~ng aithetrt Grnitetim"). Siaguler forme, indttding in the
clainu, sach as
.=or. aa and "the^ include the p.hual irefennce unlesa eqaessly stetod, or
the context
clearly india0es. otkxcwise.
[01M Ualeas ataud specifically. paoxat isfers tD any biological systam, hnman
or odwr
20 animal. VVhdle examples penaie mase to hnmen applicaano. vebesinwy and
ezpeciwatal
and other applications aro included.
(91Z8] While tha syatems, traahods, etc.. herein have beea described with
specific
refaenoe to admieisttation of NMB druge, it is uadmatnod that fie syeiems sed
methnds
swght hen+in can be applied to other drug thetepies and Other processes.
Fmlbantase,
25 die systeass sed meehods taught herein can be appried heneflcislly to
modding and
conurol (advisosy and etbeeaiea) of systaes with ootrnegLgue paranteM
varietion.
[Oln] Pmm t6o foregoinp, it vriil be appmciaood tiat. aldrongb spec'd=e
embodiments
bave been discutsed baaia for putposea of ilhustraNoa, vacioua aodificailOOS
may be
mado withont deviating 5em ffia scope of the disanaion Leeia AoeardisBiy, die
90 systems and metlxxb. edc.. inelode sucb rnodificationa as vrell as ap
patnotstians and
combinatioesi of the sab}oat matter aat founh 6uein and are not Hmited except
as by the
appcndod claims or othcr elaims having adeqaace vappoet in the die¾useion
hereia.
Ab~ED 8HUT

Dessin représentatif